Mycobacterium tuberculosis possesses agonists for several Toll-like receptors (TLRs), yet mice with single TLR deletions (e.g. TLR2 or TLR4) are resistant to acute tuberculosis. MyD88-/- mice which lack a crucial adaptor molecule required for most pathways of TLR signalling were used to examine whether TLRs play any role in protection against aerogenic M. tuberculosis H37Rv infection. MyD88-/- mice failed to control mycobacterial replication and rapidly succumbed. Moreover, expression of interleukin 12, tumor necrosis factor alpha, gamma interferon, and nitric oxide synthase 2 were markedly decreased in the knockout animals. These findings, which agree closely with a previous study from this lab on Mycobacterium avium, argue that resistance to M. tuberculosis must depend on MyD88-dependent signals mediated by an as-yet-undetermined TLR or a combination of TLRs. Although IFN-gamma is essential for host control of mycobacterial infection, the mechanisms by which the cytokine restricts pathogen growth are only partially understood. LRG-47 is an IFN-inducible GTP-binding protein previously shown to be required for IFN-gamma-dependent host resistance to acute Listeria monocytogenes and Toxoplasma gondii infections. To examine the role of LRG-47 in control of mycobacterial infection, LRG-47(-/-) and wild-type mice were infected with Mycobacterium avium, and host responses were analyzed. LRG-47 protein was strongly induced in livers of infected wild-type animals in an IFN-gamma-dependent manner. LRG-47(-/-) mice were unable to control bacterial replication, but survived the acute phase, succumbing 11-16 wk postinfection. IFN-gamma-primed, bone marrow-derived macrophages from LRG-47(-/-) and wild-type animals produced equivalent levels of TNF and NO upon M. avium infection in vitro and developed similar intracellular bacterial loads. In addition, priming for IFN-gamma production was observed in T cells isolated from infected LRG-47(-/-) mice. Importantly, however, mycobacterial granulomas in LRG-47(-/-) mice showed a marked lymphocyte deficiency. Further examination of these animals revealed a profound systemic lymphopenia and anemia triggered by infection. As LRG47(-/-) T lymphocytes were found to both survive and confer resistance to M. avium in recipient recombinase-activating gene-2(-/-) mice, the defect in cellular response and bacterial control in LRG-47(-/-) mice may also depend on a factor(s) expressed in a nonlymphocyte compartment. These findings establish a role for LRG-47 in host control of mycobacteria and demonstrate that in the context of the IFN-gamma response to persistent infection, LRG-47 can have downstream regulatory effects on lymphocyte survival.